Cutaneous leishmaniasis (CL) has a long history in West Africa, but one of the less recognized parasitic infections in the region. The disease is endemic Saharan desert countries in the North, in Sahelian band from west to East Africa. Currently, there is no vaccine against the diseases. However, studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, 3 sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). The hypothesis underlying this proposal is that a combination of parasite, vector, and human exposure to other parasitic infection such as infection with microfilariae determine the immunomodulatory effects of candidate vaccines, specifically sand fly proteins. The proposal seeks to 1] understand the basic epidemiology of cutaneous leishmaniasis and its vector in different foci of West Africa; 2] understand mechanism of resistance/susceptibility to the disease; 3] assess how an active infection with microfilariae alters the human immune response to sand fly salivary proteins and 4] reinforce local research capacity for future vaccine trials. RELEVANCE: This proposal is directly relevant to public health because Leishmaniasis take an enormous toll across the globe. Its goals are to examine the epidemiology, transmission of cutaneous leishmaniasis and a component that has been largely overlooked: the immuno-modulation of sandfly proteins. Project 1: Epidemiology of Cutaneous Leishmaniasis Project Leader: Ousmane Faye, MD, PhD (Description as provided by applicant): Leishmaniasis is a vector-borne disease transmitted to the host via the bite of a Leishmania infected phlebotomine sand fly. Cutaneous leishmaniasis (CL) has a long history in West Africa, but is one of the less recognized parasitic infections in the region. Studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, three sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). This project seeks to 1] Determine the prevalence/incidence (of infection and disease) of CL and characterize the Leishmania parasites circulating in Malian and Ghanaian classical and cryptic foci of CL; 2] Correlate specific human immune responses to sand fly salivary proteins with CL outcome. In the Aim 1 we will possibly characterize new species of Leishmania parasites from a site where the infected individuals presented with asymptomatic CL and compare it to a classical CL focus. We will also in Aim 2, for the first time, establish if sand fly salivary cellular immunity can influece the CL outcome in endemic populations. RELEVANCE: This project is at the center of the entire proposal because it will assess the relationship between human exposure to sand fly vector bite (Project 2), the parasite and immune response to sand fly salivary proteins (Project 3) and the disease. Understanding of these relationship is important for vaccine development and field trials of control strategies.